Gallbladder cancer treatment using adenovirus expressing the HGF/NK4 gene in a peritoneal implantation model

Abstract

Gallbladder cancer cells are stimulated by hepatocyte growth factor (HGF) in vitro and in vivo. We constructed an adenovirus vector, AdCMV.NK4, carrying the HGF antagonist HGF/NK4 (NK4) and evaluated whether or not this vector can suppress the peritoneal implantation of gallbladder cancer in a novel peritoneal injury mouse model. A human gallbladder cancer cell line (GBd1) and human peritoneal mesothelial cells infected with the adenovirus vector produced a substantial level of NK4 protein. An invasion of GB-d1 cells was determined by a coculture with AdCMV.NK4-infected human mesothelial cells in vitro. Both the invasion and migration of GB-d1 cells were dramatically inhibited by this vector in a multiplicity of infection (MOI)-dependent manner. GB-d1 cells were intraperitoneally injected into the nude mice with peritoneal injury, followed by either AdCMV.NK4 or a control vector (AdCMV.LacZ). The incidence and the size of the metastatic tumor drastically decreased by AdCMV.NK4 (MOI 100: n ¼ 4, Po.0001). Real-time PCR analysis revealed a transient elevation of mouse HGF mRNA expression at the peritoneal injury sites. AdCMV.NK4 has been suggested to induce the inhibition of the implantation and growth of gallbladder cancer cells in vivo through its anti-HGF activity, and the use of NK4 gene transfer could be an effective modality for preventing peritoneal metastasis of gallbladder cancer.

Suppression of metastasis of human pancreatic cancer to the liver by transportal injection of recombinant adenoviral NK4 in nude mice

“…[28][29][30][31][32] These data indicate that NK4 is certainly effective for various types of carcinoma.…”

Regulation of cell proliferation and migration in gallbladder cancer by zinc finger X-chromosomal protein

“…Most of the patients tend to demonstrate unresectable disease at the time of surgical evaluation because of the rapid invasive and metastatic progression of this cancer. Therefore, surgical treatment becomes ineffective and new treatments, such as gene therapy, are desperately needed (Dong et al, 2011a;Fukuda et al, 2003;Tanaka et al, 2004).…”

Inhibition of angiogenesis and HGF-cMET-elicited malignant processes in human hepatocellular carcinoma cells using adenoviral vector-mediated NK4 gene therapy

“…39 So far, NK4 gene therapy has demonstrated efficacy in tumor models in which the involvement of the HGF-cMET signaling pathway in pathogenesis has been clearly established. [8][9][10][11][12][13][14][15][16][17][18][19][20] Based on the multifunctional properties of NK4 on various growth factors, 3,4,12,40 we propose that NK4 gene therapy would have therapeutic value for a wider range of tumors than only cMET overexpressing carcinomas. However, application of NK4 gene therapy to specific tumor types such as HCC for which the effect of the HGF-cMET signaling is less explicit or may even be inhibitory on carcinogenesis [32][33][34] needed further assessment.…”

“…[3][4][5][6] NK4, which consists of the N-terminal hairpin domain and the four subsequent kringle domains of HGF, competitively inhibits the multiple biological activities of HGF through binding to cMET and is suggested to have a broad antiangiogenic activity through its kringle domain structure. 3,4,7 Previous in vivo studies confirmed therapeutic efficacy of NK4 gene therapy for glioblastoma, prostate, breast, gastric, pancreatic, gall bladder and colon cancers [8][9][10][11][12][13][14][15][16][17][18][19][20] and recommended further preclinical evaluation of NK4 gene therapy as anticancer agent. However, NK4 gene therapy for treatment of HCC could be argued against because the antitumor effects of NK4 in part rely on its antagonistic activity to HGF 3 and the role of the HGF-cMET system in hepatocarcinogenesis has not been clearly established.…”